Estrogen receptor α (ERα) is a member of the steroid/nuclear receptor family of transcription regulators and mediates cell growth and metastases, and resistance to apoptosis and immunosurveillance (see references 1-5). ERα is activated by binding of 17β-estradiol (E2), or by the EGF-activated ERK pathway and other signal transduction pathways (6). ERα mediated gene transcription contributes to the development and spread of breast, uterine and liver cancer (5,7,8). A role for ER action in ovarian cancer is supported by the recent finding that endocrine therapy is effective against relapsed ER containing ovarian cancers (9,10). Aromatase inhibitors that inhibit estrogen production and tamoxifen (Tam) and other Selective Estrogen Receptor Modulators (SERMs) are mainstays in treatment of estrogen-dependent cancers and have played an important role in developing our understanding of ER action (5,7,11,12). Tam and other SERMs work by competing with estrogens for binding in ER's ligand-binding pocket. Over time, tumors usually become resistant to tamoxifen and other SERMs (13-15), requiring new strategies to inhibit ERα action.
In a characterization of ER action, ERα activates gene transcription by binding to palindromic estrogen response element (ERE) DNA and ERE half sites (4,16,17). Thus, an alternative to current approaches that primarily target ER action at the level of ligand binding, is to target ERα at the level of its interaction with ERE DNA. This approach was questioned because small molecules may not disrupt the large interaction surfaces of protein-DNA and protein-protein complexes (18). Certain studies describe using a high throughput screening (HTS) approach to identify small molecules that act directly at the binding interface, or allosterically by inducing a conformational change in the protein that alters the formation of a functioning macromolecular interface (19-24). Although it was not identified by HTS, disulfide benzamide (DIBA), an ERα zinc finger inhibitor (25) enhances the antagonist activity of tamoxifen (26). In our efforts, we further developed an approach of identifying small molecule inhibitors targeting novel sites in ER action. This led to successful discoveries such as the development of compositions and methods for stimulating or inhibiting nuclear receptor hormone function.
In the field of nuclear receptors, steroid receptors, including, e.g., estrogen, androgen, and progesterone pathways, there remains a significant need for new and/or improved compositions and methods. In part an object of the invention is to meet such needs, for example by providing compositions and methods in connection with therapeutic applications. Further objects and aspects of the invention are described herein and will be apparent to one of ordinary skill in the art.